Glycogen storage disease type -
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Glycogen Storage Disease Type 1 von Gierke. What is Liver Disease? How Many People Have Liver Disease? Facts at-a-Glance Also known as von Gierke disease , is a more severe form of Glycogen Storage Disease.
All Glycogen Storage diseases together affect fewer than 1 in 40, persons in the United States. Information for the Newly Diagnosed What are the symptoms of GSD I?
What causes GSD I? How is GSD I diagnosed? How is GSD I treated? Glycogen storage disease type I also known as GSDI or von Gierke disease is an inherited disorder caused by the buildup of a complex sugar called glycogen in the body's cells.
The accumulation of glycogen in certain organs and tissues, especially the liver, kidneys, and small intestines, impairs their ability to function normally.
Signs and symptoms of this condition typically appear around the age of 3 or 4 months, when babies start to sleep through the night and do not eat as frequently as newborns.
Affected infants may have low blood sugar hypoglycemia , which can lead to seizures. They can also have a buildup of lactic acid in the body lactic acidosis , high blood levels of a waste product called uric acid hyperuricemia , and excess amounts of fats in the blood hyperlipidemia.
As they get older, children with GSDI have thin arms and legs and short stature. An enlarged liver may give the appearance of a protruding abdomen. The kidneys may also be enlarged. Affected individuals may also have diarrhea and deposits of cholesterol in the skin xanthomas.
People with GSDI may experience delayed puberty. Beginning in young to mid-adulthood, affected individuals may have thinning of the bones osteoporosis , a form of arthritis resulting from uric acid crystals in the joints gout , kidney disease, and high blood pressure in the blood vessels that supply the lungs pulmonary hypertension.
Females with this condition may also have abnormal development of the ovaries polycystic ovaries. In affected teens and adults, tumors called adenomas may form in the liver.
Adenomas are usually noncancerous benign , but occasionally these tumors can become cancerous malignant. Researchers have described two types of GSDI, which differ in their signs and symptoms and genetic cause. These types are known as glycogen storage disease type Ia GSDIa and glycogen storage disease type Ib GSDIb.
Two other forms of GSDI have been described, and they were originally named types Ic and Id. However, these types are now known to be variations of GSDIb; for this reason, GSDIb is sometimes called GSD type I non-a.
Many people with GSDIb have a shortage of white blood cells neutropenia , which can make them prone to recurrent bacterial infections.
Neutropenia is usually apparent by age 1. Many affected individuals also have inflammation of the intestinal walls inflammatory bowel disease. People with GSDIb may have oral problems including cavities, inflammation of the gums gingivitis , chronic gum periodontal disease, abnormal tooth development, and open sores ulcers in the mouth.
The neutropenia and oral problems are specific to people with GSDIb and are typically not seen in people with GSDIa. The overall incidence of GSDI is 1 in , individuals. GSDIa is more common than GSDIb, accounting for 80 percent of all GSDI cases.
This dephosphorylation reaction produces free glucose and free PO 4 anions. The free glucose molecules can be transported out of the liver cells into the blood to maintain an adequate supply of glucose to the brain and other organs of the body.
Glycogenolysis can supply the glucose needs of an adult body for 12—18 hours. When fasting continues for more than a few hours, falling insulin levels permit catabolism of muscle protein and triglycerides from adipose tissue. The products of these processes are amino acids mainly alanine , free fatty acids , and lactic acid.
Free fatty acids from triglycerides are converted to ketones , and to acetyl-CoA. Amino acids and lactic acid are used to synthesize new G6P in liver cells by the process of gluconeogenesis. The last step of normal gluconeogenesis, like the last step of glycogenolysis, is the dephosphorylation of G6P by glucosephosphatase to free glucose and PO 4.
Thus glucosephosphatase mediates the final, key, step in both of the two main processes of glucose production during fasting.
The effect is amplified because the resulting high levels of glucosephosphate inhibit earlier key steps in both glycogenolysis and gluconeogenesis. The principal metabolic effects of deficiency of glucosephosphatase are hypoglycemia , lactic acidosis , hypertriglyceridemia , and hyperuricemia.
The hypoglycemia of GSD I is termed "fasting", or "post-absorptive", usually about 4 hours after the complete digestion of a meal. This inability to maintain adequate blood glucose levels during fasting results from the combined impairment of both glycogenolysis and gluconeogenesis. Fasting hypoglycemia is often the most significant problem in GSD I, and typically the problem that leads to the diagnosis.
Chronic hypoglycemia produces secondary metabolic adaptations, including chronically low insulin levels and high levels of glucagon and cortisol. Lactic acidosis arises from impairment of gluconeogenesis.
Accumulation of G6P inhibits conversion of lactate to pyruvate. The lactic acid level rises during fasting as glucose falls. In people with GSD I, it may not fall entirely to normal even when normal glucose levels are restored. Hypertriglyceridemia resulting from amplified triglyceride production is another indirect effect of impaired gluconeogenesis, amplified by chronically low insulin levels.
During fasting, the normal conversion of triglycerides to free fatty acids, ketones, and ultimately acetyl-CoA is impaired. Triglyceride levels in GSD I can reach several times normal and serve as a clinical index of "metabolic control".
Hyperuricemia results from a combination of increased generation and decreased excretion of uric acid , which is generated when increased amounts of G6P are metabolized via the pentose phosphate pathway. It is also a byproduct of purine degradation.
Uric acid competes with lactic acid and other organic acids for renal excretion in the urine. In GSD I increased availability of G6P for the pentose phosphate pathway, increased rates of catabolism, and diminished urinary excretion due to high levels of lactic acid all combine to produce uric acid levels several times normal.
Although hyperuricemia is asymptomatic for years, kidney and joint damage gradually accrue. High levels of lactic acid in the blood are observed in all people with GSD I, due to impaired gluconeogenesis. Symptoms of lactic acidosis include vomiting and hyperpnea , both of which can exacerbate hypoglycemia in the setting of GSD I.
In cases of acute lactic acidosis, patients need emergency care to stabilize blood oxygen, and restore blood glucose. Proper identification of lactic acidosis in undiagnosed children presents a challenge, since the first symptoms are typically vomiting and dehydration, both of which mimic childhood infections like gastroenteritis or pneumonia.
Moreover, both of these common infections can precipitate more severe hypoglycemia in undiagnosed children, making diagnosis of the underlying cause difficult.
As elevated lactate persists, uric acid, ketoacids , and free fatty acids further increase the anion gap. In adults and children, the high concentrations of lactate cause significant discomfort in the muscles. This discomfort is an amplified form of the burning sensation a runner may feel in the quadriceps after sprinting, which is caused by a brief buildup of lactic acid.
Proper control of hypoglycemia in GSD I eliminates the possibility for lactic acidosis. High levels of uric acid often present as a consequence of elevated lactic acid in GSD I patients.
When lactate levels are elevated, blood-borne lactic acid competes for the same kidney tubular transport mechanism as urate, limiting the rate that urate can be cleared by the kidneys into the urine.
If present, increased purine catabolism is an additional contributing factor. In some affected people, the use of the medication allopurinol is necessary to lower blood urate levels. Consequences of hyperuricemia among GSD I patients include the development of kidney stones and the accumulation of uric acid crystals in joints, leading to kidney disease and gout , respectively.
Elevated triglycerides in GSD I result from low serum insulin in patients with frequent prolonged hypoglycemia. It may also be caused by intracellular accumulation of glucosephosphate with secondary shunting to pyruvate , which is converted into Acetyl-CoA , which is transported to the cytosol where the synthesis of fatty acids and cholesterol occurs.
Triglycerides above the 3. In GSD I, cholesterol is typically only mildly elevated compared to other lipids.
Impairment in the liver's ability to perform gluconeogenesis leads to clinically apparent hepatomegaly. Without this process, the body is unable to liberate glycogen from the liver and convert it into blood glucose, leading to an accumulation of stored glycogen in the liver.
Hepatomegaly from the accumulation of stored glycogen in the liver is considered a form of non-alcoholic fatty liver disease.
GSD I patients present with a degree of hepatomegaly throughout life, but severity often relates to the consumption of excess dietary carbohydrate. Reductions in the mass of the liver are possible, since most patients retain residual hepatic function that allows for the liberation of stored glycogen at a limited rate.
GSD I patients often present with hepatomegaly from the time of birth. In fetal development, maternal glucose transferred to the fetus prevents hypoglycemia, but the storage of glucose as glycogen in the liver leads to hepatomegaly.
There is no evidence that this hepatomegaly presents any risk to proper fetal development. Hepatomegaly in GSD type I generally occurs without sympathetic enlargement of the spleen.
GSD Ib patients may present with splenomegaly, but this is connected to the use of filgrastim to treat neutropenia in this subtype, not comorbid hepatomegaly.
Hepatomegaly will persist to some degree throughout life, often causing the abdomen to protrude, and in severe cases may be palpable at or below the navel. In GSD-related non-alcoholic fatty liver disease, hepatic function is usually spared, with liver enzymes and bilirubin remaining within the normal range.
However, liver function may be affected by other hepatic complications in adulthood, including the development of hepatic adenomas. The specific etiology of hepatic adenomas in GSD I remains unknown, despite ongoing research.
The typical GSD I patient presenting with at least one adenoma is an adult, though lesions have been observed in patients as young as fourteen.
Adenomas, composed of heterogeneous neoplasms, may occur individually or in multiples. One reason for the increasing estimate is the growing population of GSD I patients surviving into adulthood, when most adenomas develop.
Treatment standards dictate regular observation of the liver by MRI or CT scan to monitor for structural abnormalities. Hepatic adenomas may be misidentified as focal nodular hyperplasia in diagnostic imaging, though this condition is rare.
However, hepatic adenomas in GSD I uniquely involve diffuse Mallory hyaline deposition, which is otherwise commonly observed in focal nodular hyperplasia. Unlike common hepatic adenomas related to oral contraception, hemorrhaging in GSD I patients is rare.
While the reason for the high prevalence of adenomas in GSD I is unclear, research since the s has implicated serum glucagon as a potential driver. Moreover, patients with well controlled blood glucose have consistently seen a reduction in the size and number of hepatic adenomas, suggesting that adenomas may be caused by imbalances of hepatotropic agents like serum insulin and especially serum glucagon in the liver.
Patients with GSD I will often develop osteopenia. The specific etiology of low bone mineral density in GSD is not known, though it is strongly associated with poor metabolic control.
Osteopenia may be directly caused by hypoglycemia, or the resulting endocrine and metabolic sequelae. Improvements in metabolic control have consistently been shown to prevent or reverse clinically relevant osteopenia in GSD I patients. There is some evidence that osteopenia may be connected with associated kidney abnormalities in GSD I, particularly glomular hyperfiltration.
In many cases bone mineral density can increase and return to the normal range given proper metabolic control and calcium supplementation alone, reversing osteopenia.
In adults with GSD I, chronic glomerular damage similar to diabetic nephropathy may lead to kidney failure. GSD I may present with various kidney complications. Renal tubular abnormalities related to hyperlactatemia are seen early in life, likely because prolonged lactic acidosis is more likely to occur in childhood.
This will often present as Fanconi syndrome with multiple derangements of renal tubular reabsorption, including tubular acidosis with bicarbonate and phosphate wasting. These tubular abnormalities in GSD I are typically detected and monitored by urinary calcium.
Long term these derangements can exacerbate uric acid nephropathy, otherwise driven by hyperlactatemia. In adolescence and beyond, glomerular disease may independently develop, initially presenting as glomerular hyperfiltration indicated by elevated urinary eGFR.
Enlargement of the spleen splenomegaly is common in GSD I and has two primary causes. In GSD Ia, splenomegaly may be caused by a relation between the liver and the spleen which causes either to grow or shrink to match the relative size of the other, to a lessened degree. In GSD Ib, it is a side effect of the use of filgrastim to treat neutropenia.
Intestinal involvement can cause mild malabsorption with greasy stools steatorrhea , but usually requires no treatment.
Neutropenia is a distinguishing feature of GSD Ib, absent in GSD Ia. The microbiological cause of neutropenia in GSD Ib is not well understood. Broadly, the problem arises from compromised cellular metabolism in the neutrophil, resulting in accelerated neutrophil apoptosis.
The neutropenia in GSD is characterized by both a decrease in absolute neutrophil count and diminished neutrophil function. Neutrophils use a specific G6P metabolic pathway which relies on the presence of G6Pase-β or G6PT to maintain energy homeostasis within the cell.
Official Hyperglycemia and meal planning use. gov A. gov Fuel Consumption Analysis belongs to an official storaeg Hyperglycemia and meal planning in the United Glycogenn. gov website. Share sensitive information only on official, secure websites. Glycogen storage disease type V also known as GSDV or McArdle disease is an inherited disorder caused by an inability to break down a complex sugar called glycogen in muscle cells. A lack of glycogen breakdown interferes with the function of muscle cells. GSD has two classes of cause: genetic and environmental. Glyogen GSD disaese Hyperglycemia and meal planning by any inborn error of carbohydrate Glycogen storage disease type genetically defective Natural Liver Support Remedies or hype proteins Glyvogen in these processes. In livestock, environmental GSD is caused by intoxication with the alkaloid castanospermine. However, not every inborn error of carbohydrate metabolism has been assigned a GSD number, even if it is known to affect the muscles or liver. For example, phosphoglycerate kinase deficiency gene PGK1 has a myopathic form.
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